Ezetimibe is indicated for use as monotherapy and combination therapy with statins in patients with hypercholesterolemia.

Ezetimibe is also indicated for treatment of homozygous sitosterolemia, a very rare inherited genetic disorder of the ABCG5/ABCG8 transporter protein. Phytosterols (such as sitosterol and campesterol) are not synthesized in humans and are derived entirely from the diet. Once absorbed by intestinal cells, ABCG5/ABCG8 transporters normally pump these potentially atherogenic phytosterols back into the intestinal lumen, normally resulting in <5% net absorption. Dysfunctional ABCG5/ABCG8 sterol transporters result in a net hyperabsorption of phytosterols, leading to tendinous and tuberous xanthomas and premature atherosclerosis that may or may not be accompanied by elevations in blood cholesterol levels. Ezetimibe inhibits net phytosterol absorption in these patients and is the only drug with an indication for treatment of homozygous sitosterolemia.

ABC transporters function to translocate or "pump" various compounds (such as sugars, amino acids, metal ions, peptides, proteins, and a large number of hydrophobic compounds and metabolites) across the membranes of cells and tissues. The ABC transporter superfamily is the largest transporter gene family and is typically classified into subfamilies of A–G.

Tangier disease is an inherited recessive disorder resulting from a defect in the ABCA1 transporter, which is responsible for the transport of cholesterol from peripheral tissues to HDL particles. No normal HDL exists in this disorder, and patients have very low levels of an abnormal HDL variant. Clinically, patients have yellow-orange tonsils, peripheral neuropathy, and hepatosplenomegaly thought to be related to the accumulation of cholesteryl esters in body tissues and macrophages.

Sitosterolemia is an inherited autosomal recessive disorder resulting from a defect in enterocyte ABCG5 and/or ABCG8, responsible for the transport of intestinally absorbed cholesterol and plant sterols/stanols back to the intestinal lumen. Clinically, patients express tendinous and tuberous xanthomas and premature atherosclerosis without necessarily having elevations in blood cholesterol levels.

The absorption of dietary cholesterol is variable, affected by the diet, and it has been recognized for more than 80 years that this absorption process is also highly selective. Rudolf Schoenheimer demonstrated more than 80 years ago that plant sterols were not retained by mammals, even in animals such as herbivores, which do not eat cholesterol but eat exclusively plant sterols. This mechanism is so exclusive that humans do not retain any plant sterols, a process that is disrupted in the genetic disorder of sitosterolemia.

In addition to regulation at the intestinal level, such "xenobiotic" sterols are preferentially excreted by the liver into bile, and this process may also be important for excreting cholesterol into bile. The latter is also an important feature not only for the maintenance of whole body cholesterol balance, but also for enabling appropriate bile constituent secretion to enable dietary cholesterol to be absorbed.

Bearing in mind the above physiology, Bhattacharyya and Connor described a family of two affected sisters, both of whom presented with tendon xanthomas, but who did not have any significant family history of premature coronary artery disease, and their cholesterol levels in the blood, measured by the conventional enzymatic tests, did not support a diagnosis of familial hypercholesterolemia. However, these astute clinician scientists performed sterol analyses by gas-capillary chromatography and detected in the blood of the affected sisters very large quantities of plant sterols, the major species of which was β-sitosterol. The term "β" is not necessary, since there is no biological "α."

Once this condition was described, a few more cases were identified, some in which the probands had died of premature coronary artery disease, and family analyses identified more cases of sitosterolemia. Since all the plant sterol species are highly elevated in this condition, the disease is better termed phytosterolemia, though perhaps the original terminology may survive this revision.

Investigation of a few newly diagnosed individuals showed that they hyperabsorbed all plant sterols and also seemed to hyperabsorb cholesterol, with an increase in plasma phytosterolemia and a resultant body pool expansion of cholesterol and phytosterols. Indeed, another defect that soon became evident was that, despite the expanded body pools of sterols, the liver seemed unable to excrete these sterols into bile. Bile samples obtained from a limited number of affected individuals showed an almost sterol-poor bile, suggesting that there were two defects, one at the level of the intestine and one at the level of the liver.

Plasma cholesterol and sitosterol levels were measured by capillary gas liquid chromatography or high-performance liquid chromatography (HPLC). Only in 4 children were the plasma cholesterol levels very high (and these children were typically referred to as having "pseudohomozygous familial hypercholesterolemia"). None of the adult patients had any significant hypercholesterolemia, compared with parents, unaffected siblings, or random controls. On the other hand, plasma sitosterol levels were very elevated and are regarded as the "gold standard" for diagnosis.

Thus the loss of a single locus (since sitosterolemia has an autosomal recessive pattern of inheritance) leads to a loss of sterol discrimination at the intestinal level and a loss of ability to excrete sterols into bile. In limited studies of liver biopsy samples from affected individuals, the cholesterol synthesis pathway was reduced, as was the bile salt synthesis pathway, although a discordant increase in the LDL-receptor pathway has been reported. The elucidation of this defect will lead to a greater insight into normal physiology.

Although the initial report of sitosterolemia did not indicate the presence of premature coronary artery disease, subsequently two probands presented with either sudden cardiac death, or angina followed by sudden cardiac death; both were less than 20 years of age.

Thus, based upon the known physiology in healthy individuals and the observed defects in patients with sitosterolemia, we proposed that the gene defect was one that not only regulated cholesterol entry at the intestinal level and excretion at the hepatic biliary level, but also could discriminate between cholesterol and noncholesterol for these processes.